Role of Sphingolipids in Cardiac Ischemia

描述（由申请人提供）：急性心脏缺血如心肌梗死（MI）是美国死亡的主要原因之一。迄今为止，还没有fda批准的药物可以通过直接干扰细胞死亡过程来减小梗死面积或阻止心肌梗死的进展。大多数治疗包括药物治疗（如TPA）或程序性治疗（如血管成形术），目的是对缺血心肌进行再灌注。有证据表明，细胞死亡过程中的一个非常早期的事件涉及神经鞘脂信号分子的激活，这些信号分子对心脏细胞有很大的损害。该SBIR I期和II期研究的目标是证明鞘磷脂酶（nSMase）的中性形式及其适配蛋白FAN（与中性SMase激活相关的因子）是心肌缺血患者心脏保护治疗的有效靶点。这些信号成分位于MAP激酶、半胱天冬酶和死亡过程的原促癌基因的上游。除了验证靶点外，我们还打算阐明关键鞘脂信号分子在产生与急性心肌缺血相关的负性肌力和细胞死亡中的作用机制。在第一阶段的工作中，我们打算在缺乏鞘脂信号系统这些重要成分的FAN和nSMase敲除小鼠中手术制造可逆性心脏梗死。在这种缺血/再灌注（IR）损伤模型中，与对照组相比，如果KO小鼠的FAN/nSMase信号系统不起作用，那么梗死面积占风险区域的百分比预计会减少。这些方法将与我们的心肌细胞培养IR损伤模型结合使用，为FAN/SMase信号系统是急性心脏缺血的关键原因提供额外的原理证明

DESCRIPTION (provided by applicant): Acute cardiac ischemia such as myocardial infarction (MI) is one of the leading causes of death in the US. To date, there are no FDA-approved drugs that reduce the size of the infarct or prevent the progression to MI by directly interfering with the cell death process. Most treatments involve either medical (e.g., TPA) or procedural (e.g., angioplasty) treatments intended to reperfuse the ischemic myocardium. Evidence suggets that a very early event in the cell death process involves activation of sphingolipid signaling molecules that are largely damaging to cardiac cells. It is the goal of the proposed work in both Phase I and Phase II of this SBIR is to prove the principle that the neutral form of sphingomyelinase (nSMase) and its adaptor protein, FAN (factor associated with neutral SMase activation), are valid targets for cardioprotective therapy in patients with myocardial ischemia.These signaling components are up-stream of the MAP kinases, caspases and proto-onogenes of the death process. In addition to validating the targets, we intend to elucidate the mechanisms of action of key sphingolipid signaling molecules in producing the negative inotropy and cell death associated with acute cardiac ischemia. In Phase I of the work, we intend to surgically produce reversible cardiac infarcts in FAN and nSMase knockout mice lacking these important components of the sphingolipid signaling system. In this model of ischemia/reperfusion (IR) injury, infarct sizes as a percentage of areas of risk are expected to be reduced if the FAN/nSMase signaling system is non-functional in the KO mouse compared to control litermates. These methods will be used in conjunction with our cardiomyocyte cell culture model of IR injury provide additional proof-of-principle that the FAN/SMase signaling system is key causal factor in acute cardiac ischemia